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History and Sequence of Events for the SGLT-2 Inhibitors

Dec 15, 2016

2016 could be remembered for the year when the diabetes class of drugs known as the SGLT-2 inhibitors has made a huge impact on the lives of those with type 2 diabetes today and into the future.

Never in the history of the treatment for diabetes have we seen a new drug entry that reduce the risk for dying for those with diabetes.

Let’s take a look at the sequence of events leading up to the major announcement that the SGLT-2 inhibitor drug can help prevent DEATH and CVD for those that have the greatest risk of dying from diabetes.

Surprise — or maybe not so much! With the Centers for Disease Control and Prevention estimating that 29.1 million people in the U.S. have diabetes, of whom more than 90% have type 2 diabetes, it may come as little shock that diabetes treatment is expected to be the third fastest-growing drug class over the next five years at 8% to 11% per year. In dollar terms, estimates 2021 spending on diabetes drugs will fall between $95 billion and $110 billion. Innovation is certainly not hard to find in the diabetes space, specifically in the drug and device categories. Arguably the biggest improvement over the past couple of years has been the introduction of SGLT-2 inhibitors. Prior generations of diabetes medications worked in the liver or pancreas. SGLT-2 inhibitors do their work in the kidneys by blocking glucose absorption in an effort to control blood sugar levels for type 2 diabetics. Aside from meeting clinical efficacy standards, the SGLT-2 class of diabetes drugs has presented with pleasant side effects that include lowered systolic blood pressure and weight loss. Not all type 2 diabetics are overweight or have hypertension, but the correlation is more common than not, giving SGLT-2 drugs a potentially bright future. Furthermore, Eli Lilly and its partner Boehringer Ingelheim have really stood out for their SGLT-2 inhibitor Jardiance. In their long-term cardiovascular outcomes trial known as EMPA-REG OUTCOME, Jardiance led to a 32% relative reduction in the risk of death from all causes. It was the first diabetes medication that had led to a statistically significant reduction in the risk of all-cause and cardiovascular-related death.  And the studies have shown that most people with Type 2 diabetes will die from stroke or heart attack and not directly from diabetes.

So what might be in the future for the new class of diabetes drugs?  It could be Lexicon Pharmaceuticals that could have the next eye-popping diabetes drug, Sotagliflozin. Sotagliflozin is a dual inhibitor of SGLT-1 (which works in the intestines) and SGLT-2, and it fairly recently met its primary endpoint in a phase 3 study for type 1 diabetes. Both doses, the once-daily 200 mg and once-daily 400 mg, led to statistically significant reductions in A1C (a test that measures glucose levels over time) of 0.43% and 0.49%, respectively, compared to just 0.08% for the placebo. Type 2 diabetes is a considerably larger market, meaning sotagliflozin could be a star if successful.

In looking at just what has happened over this year 2016, we can see a lot has been discovered:

  1. Feb 19, 2016: Cardiovascular Effects of Dapagliflozin in Patients with Type 2 Diabetes and Different Risk Categories: a Meta-Analysis. Abstract link. See also: Cardiovascular Impact of Dapagliflozin. Blood Pressure and Glycemic Effects of Dapagliflozin versus Placebo in Patients with Type 2 Diabetes on Combination Antihypertensive Therapy: a Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study. Abstract link.
  1. March 2016: FDA Expands Indication of INVOKAMET® (canagliflozin/metformin HCl) to Include First-Line Treatment of Adults with Type 2 Diabetes. Press release. Initial Combination Therapy with Canagliflozin Plus Metformin Versus Each Component as Monotherapy for Drug-Naïve Type 2 Diabetes Abstract link. See also: Rosenstock J, et al. Diabetes Care. 2016 Mar;39(3):353-362.
  1. May 18, 2016 : Canagliflozin (Invokana, Invokamet): Drug Safety Communication – Clinical Trial Results Find Increased Risk of Leg and Foot Amputations. FDA communication. **** Lack of Evidence for a Harmful Effect of Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors on Fracture Risk among Type 2 Diabetes Patients: a Network and Cumulative Meta-Analysis of Randomized Controlled Trials. Abstract link. See also: Do SGLT2 Inhibitors Really Increase Fracture Risk?
  1. May 24, 2016: Efficacy and Safety of Canagliflozin in Individuals Aged 75 and Older with Type 2 Diabetes Mellitus: a Pooled Analysis. Abstract link. See also: Can Older Patients Tolerate Canagliflozin? **** U.S. FDA Approves INVOKAMET® XR (Canagliflozin / Metformin Hydrochloride Extended-Release) for the Treatment of Adults with Type 2 Diabetes. Press release.
  1. June 14, 2016 SGLT2 Inhibitors: PRAC Makes Recommendations to Minimize Risk of Diabetic Ketoacidosis. Abstract Link. See also: New EMA Alert Regarding SGLT2 Inhibitors. **** FDA Strengthens Kidney Warnings for Diabetes Medicines Canagliflozin (Invokana, Invokamet) and Dapagliflozin (Farxiga, Xigduo XR). Abstract Link
  1. June 28, 2016: Heart Failure Outcomes with Empagliflozin in Patients with Type 2 Diabetes at High Cardiovascular Risk: Results of the EMPA-REG OUTCOME® Trial. Abstract link. See also: Heart Failure Outcomes Across Type 2 Diabetes Groups. **** FDA Advisory Committee Recommends Approval of Jardiance® (Empagliflozin) for Cardiovascular Indication in 12-11 Vote. Press release.  FDA Advisory Committee recommends approval of Jardiance® (empagliflozin) for cardiovascular indication in 12-11 vote.
  1. Sept 6, 2016 SGLT-2 Receptor Inhibitors for Treating Patients with Type 2 Diabetes Mellitus: a Systematic Review and Network Meta-Analysis. Abstract Link. Sodium-Glucose Co-Transporter 2 Inhibitors in Addition to Insulin Therapy for Management of Type 2 Diabetes Mellitus: a Meta-Analysis of Randomized Controlled Trials. Abstract link. See also Adding SGLT2 Inhibitors to Insulin.
  1. Nov, 2016  “Canagliflozin Provides Greater Attainment of Both HbA1c and Body Weight Reduction versus Sitagliptin in Patients with Type 2 Diabetes. Abstract link. See also: HbA1c and Weight: Canaglioflozin vs Sitaglitpin. **** A Post-Hoc Analysis of the Comparative Efficacy of Canagliflozin and Glimepiride in the Attainment of Type 2 Diabetes-Related Quality Measures. Abstract Link.
  1. December, 2016” Exenatide Once Weekly Plus Dapagliflozin Once Daily versus Exenatide or Dapagliflozin Alone in Patients with Type 2 Diabetes Inadequately Controlled with Metformin Monotherapy (DURATION-8): a 28 Week, Multicentre, Double-Blind, Phase 3, Randomized Controlled Trial. Abstract link. Comparison between SGLT2 Inhibitors and DPP4 Inhibitors Added to Insulin Therapy in Type 2 Diabetes: a Systematic Review with Indirect Comparison Meta-Analysis. Abstract link. See also: SGLT2 Inhibitors or DPP-4 Inhibitors with Insulin.
  1. On December 2, 2016, The U.S. Food and Drug Administration (FDA) approved a new indication for Jardiance® (empagliflozin) tablets to reduce the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease. JARDIANCE is the first type 2 diabetes treatment approved with this additional indication and the only oral type 2 diabetes medicine shown in a clinical trial to provide a life-saving cardiovascular benefit. JARDIANCE is marketed by Boehringer Ingelheim and Eli Lilly and Company FDA News Release on Reduction of Death
  1. What’s next?